Health Hazard

Gag the messenger

Drug companies hunt for research that will praise their product, pushing money at academics whose work looks promising. But within the research contract there is usually a gag clause that prevents the researcher from spilling the beans if the results are bad – as Betty Dong found out to her great cost.

Dong, a professor of clinical pharmacology at the University of California, was approached by Flint Pharmaceuticals (later acquired by Boots Pharmaceuticals) because she had published a small study in 1988 which suggested that Flint’s premium-priced thyroid medication Synthroid might have the upper hand over competing drugs. Anxious for more, Flint gave Dong $250,000 to conduct a trial comparing the drug with three generic competitors. Flint’s scientists also helpfully designed the protocols for her research. But when Dong’s study concluded that Synthroid was actually no better than the others, Boots reminded the scientist that her contract contained a clause allowing them final say over her right to publish.

A seven-year campaign ensued to discredit Dong and to stop her publishing the results. In 1995, she withdrew a paper from the Journal of the American Medical Association after being threatened with legal action. That same year Boots was gobbled up by Knoll Pharmaceuticals (a division of the German chemical giant BASF) who then published an ‘interpretation’ of Dong’s data by a doctor in their pay. After further legal wrangles and media exposés, Dong finally managed in 1997 to publish her work. Knoll was promptly sued on behalf of Synthroid users who had paid out an estimated extra $365 million per year for a drug that they had been misled into believing was superior. Knoll settled out of court for $98 million – but seven years of gagging Dong had earned the makers of Synthroid an estimated $2.45 billion.

Foreign bodies

Abbott Laboratories produced urokinase, a drug primarily used to dissolve blood clots which was derived from the kidneys of dead human newborns and foetuses, under the brand name Abbokinase. The more rational among us might remember that numerous medicinal products have sources that cause us unease, and balance that against their beneficial potential. But Abbokinase ran into trouble with the US Food and Drug Administration (FDA) in the late 1990s for reasons that had little to do with squeamishness.

Abbott had contracted another company, BioWhittaker, to produce the drug for them. When the FDA inspected BioWhittaker in mid-1998 the agency was alarmed to find that the company had not properly segregated human kidney cells from ‘potentially infectious material of human and animal origins’ including monkeys, cats and rabbits. The FDA also found that Abbott Labs was not doing enough to remove potential viruses from the organic material used for the drug. After first halting shipments, the FDA allowed the drug to be sold with the warning: ‘The kidney cells used in the manufacture of this product were obtained from populations at high risk of a variety of infectious diseases, including tropical diseases.’

In February 1999 the activist group Public Citizen’s Health Research Group reported, after studying FDA inspection reports and interviewing many FDA staffers, that they believed Abbokinase had been derived from babies and foetuses from a single hospital in Cali, Colombia. The FDA stopped Abbokinase again a few months later due to contamination fears. But the bigger issue for many was the lack of any evidence that consent had been obtained from the parents of the neonates, let alone screening for diseases. One patient who had received Abbokinase several times following a bone marrow transplant was disturbed by the fact that just one hospital had provided enough kidney tissue for a drug that had sales of $250 million in 1998.

Abbokinase is now back on the market. Abbott states in its product information that all kidney cells are now sourced exclusively from dead babies (birth to 28 days) in the US. ‘Kidney donations’ are mentioned, but there is no explicit mention of informed consent.

Turf Wars

Until 1999 pharma giant Novartis enjoyed a monopoly for the drug cyclosporine, used to prevent organ rejection in kidney, liver and heart transplant patients.

But when rivals started producing generic versions, and selling them at a fraction of the price to cash-strapped public-health authorities in Latin America, Novartis went into overdrive.

It began legal proceedings to force Abbott Laboratories to withdraw their generic version, Gengraf, from the market, claiming that Abbott was using microemulsion technology invented and patented by Novartis.

Then, rumours started flying that the generic drugs could be dangerous, even lethal to patients. Panic spread, especially in Latin America. Patient groups in Brazil demanded that their public health services keep providing the twice-as-expensive Novartis brand drug, Neoral.

In Brazil, where there are 8,000 users of cyclosporine, the Federation of Associations of Patients with Kidney Disease and Kidney Transplants claimed that a study, showing that the Brazilian generic Sigmasporin was just as effective as the Novartis drug, had been falsified. Sigma Labs, the company that produces Sigmasporin, said that Novartis was out to discredit their product. Abbott Labs, too, rejected Novartis’ accusations and guaranteed that its product was the bioequivalent of the Novartis drug, Neoral.

Brazilian health minister José Serra went further, claiming that Novartis was manipulating patients. He also claimed that the company had been funding NGOs and patients’ groups to lobby for Neoral which was commanding ‘abusive prices’ in Brazil.

By July 2002 it looked as if Novartis was winning in the courts. It managed to persuade a US jury that Abbott had infringed the Novartis patent in its production of cyclosporine. Then in March 2003 a Delaware judge overruled the jury’s verdict. Novartis plans to appeal.

Meanwhile, Costa Rica’s national health authority has promised to provide Neoral for another year before switching to Abbott’s Gengraf – at half the cost. And in Mexico the row continues with patients’ groups demanding the Novartis drug instead of the Mexican generic, Zavan Me, which they claimed could be lethal.

Testing Times

Trials for new drugs are exploding in the Majority World – particularly in Latin America, the former Soviet republics and Southern Africa. These tests, often licensed to research organizations on behalf of Western drug companies, have come under fire for giving inadequate information to subjects and for carrying out risky procedures which would not be approved in the West. The reasons for shifting these trials are obvious – low costs, lax regulations and a large pool of untreated, often illiterate, patients who see the trials as offering them better ‘foreign’ treatment.

During a 1996 outbreak of meningitis in Nigeria, Pfizer flew in a team to test a new drug, trovafloxacin (Trovan). The trials were hastily set up at a time of desperate need and the parents of the sick children on whom the drug was tested did not give their written consent, according to an exposé by Britain’s Channel 4 TV. Pfizer claimed that many of the parents could not read or write; the parents claim they were never asked.

There was also no approval by an independent Ethics Commission – although Pfizer produced a backdated letter from a Commission that wasn’t even in existence when the letter was supposed to have been written. Pfizer’s own childhood diseases specialist wrote a letter to the company’s Chairperson protesting that Trovan had never been tested before for the strain of meningitis concerned. He was sacked shortly afterwards. Eleven children died during the trials. Others are suffering known side effects of the drug. Pfizer maintains this was not due to the drug or the treatment they received from the Pfizer team. Thirty of the families concerned have taken Pfizer to court.

This year GlaxoSmithKline and the Malaria Vaccine Initiative (MVI, funded by the Gates Foundation) provided funds for a malaria vaccine to be tested in Mozambique on 2,000 children under five. The vaccine contains protein from the malaria parasite, ‘a fragment of hepatitis B’ and a ‘helping agent’. While a malaria vaccine is highly desirable (the disease kills 3,000 African children a day) there are niggling questions. What is the helping agent’s toxicity, seeing as it is not licensed in the US? What about informed consent? The company claims that 71 per cent of adults tested were protected by the drug – but the protection wore off after just two months. Melinda Moree, director of the MVI, admits that the trial was unlikely to succeed, but that even negative results further research. Would Ms Moree expose her child to an experimental vaccine, knowing it was likely to fail?

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